East German Pat. No. 67,130 to Becker et al describes a procedure for the synthesis of 3,5-disubstituted-1,2,4-triazoles useful as intermediates and having the following structure ##STR1## wherein R.sub.1 is alkyl, aryl, aralkyl, alkoxyalkyl, acylaminoalkyl, or a heterocyclic group and R.sub.2 is hydrogen, alkyl, or aryl.
Becker et al in a paper entitled "A Novel Synthesis for 3-Substituted 1,2,4-Triazoles," Journal fur praktische Chemie. Volume 311, 1969, pages 477-489, disclose the preparation of 3-substituted-1,2,4-triazoles including 3-phenyl-1,2,4-triazoles of the structure ##STR2## wherein R.sup.1 can be ethoxy, methyl, ethyl or n-propyl. A general preparation for 1-acetyl-3-phenyl-1,2,4-triazole and 1-propionyl-3-phenyl-1,2,4-triazole is set out on page 487.
U.S. Pat. No. 4,006,159 to Newman discloses mixtures of acyl-substituted 1,2,4-triazole-3-carboxamides which may be presented by the following structural formulae: ##STR3## WHEREIN EACH MIXTURE CONSISTS OF ALL THREE FORMS WHEREIN R is the same in each form and wherein R is hydrogen, alkyl having up to 15 carbon atoms; cycloalkyl having from 3 to 8 carbon atoms; phenyl; ortho-, meta-, or para-hydroxyphenyl; ortho-, meta-, or paramethoxyphenyl; or adamantyl. The above mixtures are said to be useful as antiviral agents.
British Specification No. 1,351,430 discloses triazoles of the formula ##STR4## wherein R and R.sub.1 are phenyl or substituted phenyl though not both simultaneously phenyl, and R.sub.2 is hydrogen or C.sub.1 -C.sub.4 alkyl, which are said to be useful as CNS depressants.
The present invention relates to a method of treating inflammatory and/or psychotic conditions with derivatives of 1,2,4-triazoles having the structure ##STR5## wherein R and R.sup.1 may be the same or different and may be lower alkyl, cycloalkyl, cycloalkyl-lower alkyl, phenyl or phenyl-lower alkyl. Where present, the phenyl whether alone or as part of a lower alkyl group may be substituted with one or two of halogen, trifluoromethyl, lower alkyl, lower alkoxy or lower alkylthio.
In addition, the present invention relates to pharmaceutical compositions for use in treating inflammatory conditions or psychotic states, the compositions containing a triazole of formula I and a pharmaceutically acceptable carrier therefor.
The preferred compounds used in the method and composition of the invention are those of formula I wherein R and R.sup.1 are each lower alkyl or phenyl or R is lower alkyl and R.sup.1 is phenyl.
The term "lower alkyl" as used herein refers to alkyl groups having 1 to 7 carbons, preferably 1 to 4 carbons, including straight or branched chain groups, such as methyl, ethyl, n-propyl, i-propyl, 2-propylbutyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, n-hexyl, and n-heptyl and the various branched chain isomers thereof.
The term "lower alkoxy" or "lower alkylthio" as used herein refers to lower alkyl groups as defined above attached to an oxygen atom or sulfur atom, respectively, with methoxy being preferred.
The term "cycloalkyl" as used herein refers to saturated carbocyclic radicals containing 3 to 7 carbons in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, optionally substituted with one lower alkyl group.
The term "halogen" as employed herein refers to chlorine, bromine, iodine or fluorine with chlorine and bromine being preferred.
The compounds of formula I are physiologically active substances which possess useful anti-inflammatory and central nervous system neuroleptic activities. They can be used in the treatment of rheumatoid arthritus and as major tranquilizers for mammalian species such as rats, dogs, monkeys, etc. For this purpose these compounds may be incorporated in a conventional dosage form such as tablet, capsule, injectable or the like, along with the necessary carrier material, excipient, lubricant, buffer or the like, as will be seen hereinafter, for oral or parenteral administration in single or divided doses of about 1 to 150 mg/kg/day, preferably about 5 to 75 mg/kg, two to four times daily.
The formula I compounds have antiinflammatory activity as measured by the mouse active arthus (MAA) test and/or other related tests and are useful as antiinflammatory agents and may be used, for example, in a manner similar to phenylbutazone or indomethacin. They may be used to decrease joint swelling, tenderness, pain and stiffness in mammalian species, e.g., in conditions such as rheumatoid arthritis.
The neuroleptic activity of the formula I compounds is illustrated by their ability to decrease avoidance behavior in rats and monkeys according to procedures similar to that of Tenen [cf. Psychon. Sci., 6, 407-408 (1966)] as well as the ability to induce hypothermia.
The compounds of formula I may be prepared according to the procedure outlined in East German Patent 67,130 (1969), Chem. Abst. 71, 124441e or a modification thereof as described below. Thus, a nitrile of the structure EQU RCN (or R.sup.1 CN) II
is condensed with an amino-1,2,4-triazole of the structure ##STR6## in the presence of an alkali metal hydride, such as sodium hydride or lithium hydride, and a nonreacting solvent such as dimethylformamide, dimethyl sulfoxide or dioxane, to form a compound of the structure ##STR7##
The formula IV compound is then reacted with an acid anhydride ##STR8## such as acetic anhydride, propionic anhydride, butyric anhydride and the like to yield compounds of formulae VI and VII ##STR9## which are then easily hydrolyzed to the formula I compound.
The starting triazole of structure IV is prepared by techniques well known in the art (e.g., see Th. Curtius and G. M. Dedichen, J. Prakt, Chem., 50, 241 (1894), Beil, 26, 29). Thus, the formula IV compound may be prepared by reaction of hydrazine and an alkyl cyanide EQU R.sup.1 CN VIII
under high temperatures ranging from 100.degree. to 250.degree., preferably from 140.degree. to 190.degree. C., for periods of 0.5 to 48 hours in a sealed system, if necessary.
A compound of formula I can be administered orally or parenterally (for example, intraperitoneally, subcutaneously, intramuscularly or intravenously). Powders can be prepared by comminuting the active ingredient with a similarly comminuted diluent such as starch or lactose. Suitable forms for oral administration include capsules, tablets, troches, elixirs, wafer, chewing gum, syrups, and a suitable form for parenteral administration in a sterile injectable. Such unit dosage forms are prepared by compounding with a conventional vehicle, excipients, binders, preservatives, stabilizers, flavoring agents or the like as called for by acceptable pharmaceutical practice. Also, the compounds used in this invention can be formulated with other pharmaceutically active compounds.
The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.